tbuckley/cabot-search huggingface dataset:
Abstract A024: Development of potent and selective nicotinamide N-methyltransferase inhibitors for kidney cancer
Authors: Rong Huang, Iredia Iyamu
Journal: Cancer Research (2023)

Abstract Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that regulates energy balance and methylation potential through the methylation of nicotinamide using S-adenosylmethionine (SAM) as the cofactor. NNMT has emerged as a novel target for both primary and metastatic ccRCC, as its high expression in ccRCC tumor tissues is linked with low survival. Meanwhile, NNMT depletion or inhibition efficiently suppresses the growth and metastasis of ccRCC in cellular and animal studies. Here, we report rational design and synthesize cell-potent and selective NNMT inhibitors with cellular IC50 values of 140 nM, representing the most cell-potent inhibitors to date. Furthermore, our NNMT inhibitors suppress renal cancer 786O and Caki-1 cell growth with a GI50 value of 9.3 and 7.3 µM, respectively. Moreover, our NNMT inhibitors reduced the migration of renal cancer cells through wound healing assay. In summary, our inhibitors would serve as valuable chemical probes to investigate the catalytical function of NNMT and evaluate the therapeutic potential of NNMT for kidney cancer. Citation Format: Rong Huang, Iredia Iyamu. Development of potent and selective nicotinamide N-methyltransferase inhibitors for kidney cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A024.
Abstract IA009: Development of HIF2 inhibitors: Bench to bedside and back
Authors: James Brugarolas
Journal: Cancer Research (2023)

Abstract Arguably the most important driver of clear cell renal cell carcinoma (ccRCC), HIF2a was traditionally regarded as undruggable. However, structural analyses at UT Southwestern Medical Center found a vulnerability leading to the identification of small molecule inhibitors, and eventually the development of highly related PT drugs by Peloton Therapeutics (PT2385 and PT2977, also called belzutifan). PT drugs bind to HIF2a and induce a conformational change that triggers its dissociation from HIF1b, thereby inhibiting DNA binding and gene transactivation. PT drugs have shown activity in patients, but resistance develops over time. Resistance mutations have been identified, initially in preclinical models, and subsequently in patients. This has spurred the development of second-generation inhibitors, including siRNA-based therapeutics. Recently, we reported a tumor-directed HIF2a-targeting siRNA drug (siHIF2) developed by Arrowhead Pharmaceuticals that effectively depleted both wild-type and mutant HIF2a. siHIF2 showed activity against ccRCC in preclinical models and in patients. Overall, these studies establish HIF2a as a core dependency and therapeutic target, and set a paradigm for tumor-directed RNA-based therapeutics in cancer. Citation Format: James Brugarolas. Development of HIF2 inhibitors: Bench to bedside and back [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA009.
Abstract PR011: Downregulation of the HIF2a target cyclin D1 underlies the efficacy of the HIF2a inhibitor belzutifan in kidney cancer
Authors: Nitin H. Shirole, Devishi Kesar, William R. Sellers, William G. Kaelin
Journal: Cancer Research (2023)

Abstract Abstract: Most clear cell renal cell carcinomas (ccRCCs) are caused by loss of the pVHL tumor suppressor function. Inactivation of pVHL leads to increased accumulation of HIF2a, which drives ccRCC in preclinical models. HIF2a interacts with ARNT and functions as a heterodimeric transcription factor. HIF2a can activate hundreds of downstream target genes, including many that are suspected of playing a role in ccRCC pathogenesis based on their biological functions. Peloton Therapeutics developed a specific allosteric HIF2a inhibitor named PT2399, which disrupts the HIF2a-ARNT interaction and silences the HIF2a transcription program. Furthermore, PT2399 suppresses the growth of ccRCC cells in in-vitro and in-vivo assays. A more advanced version of PT2399, Belzutifan, was recently approved for treating tumors in patients with germline VHL mutations (VHL disease) and is in Phase 3 testing for sporadic ccRCCs. Since HIF2a is a transcriptional activator, we hypothesized that PT2399’s ability to suppress ccRCC is linked to repression of one or more HIF2a target genes. To identify these genes, we performed a pooled whole genome CRISPR activation (CRISPRa) screen in the presence or absence of PT2399. This screen identified multiple genes (“hits”) that, when activated, likely conferred resistance to PT2399. To further differentiate between direct vs indirect HIF2a targets that confer resistance to PT2399, we performed nascent RNA-seq (Pro-seq) after acute treatment of ccRCC cells with PT2399. Comparison of the CRISPRa and Pro-Seq data, together with secondary validation assays, identified CCND1, which encodes Cyclin D1, as a direct target gene of HIF2a that, when activated, confers complete resistance to PT2399 in multiple ccRCC cell lines. Additionally, we showed that wild-type Cyclin D1 (WT), but not a mutant (KE) that fails to activate CDK4/6, confers resistance to PT2399. Interestingly, Cyclin D1 overrides the growth inhibitory effect of PT2399 in ccRCC cells irrespective of pRB status. To identify the relevant Rb-independent substrates of Cyclin D1, we performed IP-MS experiments in RB1-/- ccRCC cells under substrate trapping conditions. Our preliminary data from these experiments suggests that RBL1 (p107) and RBL2 (p130) substitute for pRB in RB1-/- ccRCC cells. Our findings provide further support for CDK4/6 as a therapeutic target in ccRCC. Citation Format: Nitin H. Shirole, Devishi Kesar, William R. Sellers, William G. Kaelin Jr. Downregulation of the HIF2a target cyclin D1 underlies the efficacy of the HIF2a inhibitor belzutifan in kidney cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR011.
Abstract B011: An atlas of cellular heterogeneity in primary and metastatic renal cell carcinomas
Authors: Ariel Madrigal, Minjun Kim, Adrien Osakwe, Tianyuan Lu, Zohreh Mehrjoo, Elham Moslemi, Rick Farouni, Larisa Morales-Soto, Yu Chang Wang, Matthew Dankner, Haig Djambazian, Kevin Petrecca, Jonathan Spicer, Fadi Brimo, Peter Siegel, Morag Park, Jiannis Ragoussis, Simon Tanguay, Yasser Riazalhosseini, Hamed S. Najafabadi
Journal: Cancer Research (2023)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR005) of the Conference Program/Proceedings. Citation Format: Ariel Madrigal, Minjun Kim, Adrien Osakwe, Tianyuan Lu, Zohreh Mehrjoo, Elham Moslemi, Rick Farouni, Larisa Morales-Soto, Yu Chang Wang, Matthew Dankner, Haig Djambazian, Kevin Petrecca, Jonathan Spicer, Fadi Brimo, Peter Siegel, Morag Park, Jiannis Ragoussis, Simon Tanguay, Yasser Riazalhosseini, Hamed S. Najafabadi. An atlas of cellular heterogeneity in primary and metastatic renal cell carcinomas [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B011.
Selected Articles from This Issue
Journal: Clinical Cancer Research (2023)

Highlights| August 15 2023 Selected Articles from This Issue Author & Article Information Online ISSN: 1557-3265 Print ISSN: 1078-0432 ©2023 American Association for Cancer Research2023American Association for Cancer Research Clin Cancer Res (2023) 29 (16): 2949. https://doi.org/10.1158/1078-0432.CCR-29-16-HI Related Content A commentary has been published: Bavituximab Decreases Immunosuppressive Myeloid-Derived Suppressor Cells in Newly Diagnosed Glioblastoma Patients A commentary has been published: MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling A commentary has been published: Dual Targeting of Apoptotic and Signaling Pathways in T-Lineage Acute Lymphoblastic Leukemia View more A commentary has been published: Osimertinib and Selpercatinib Efficacy, Safety, and Resistance in a Multicenter, Prospectively Treated Cohort of EGFR-Mutant and RET Fusion-Positive Lung Cancers View less Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record August 15 2023 Citation Selected Articles from This Issue. Clin Cancer Res 15 August 2023; 29 (16): 2949. https://doi.org/10.1158/1078-0432.CCR-29-16-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search EGFR-mutant lung cancers can acquire RET fusion-mediated bypass resistance to osimertinib. Rotow and colleagues present the largest series of patients with these cancers who were prospectively treated in a multicenter cohort with the combination of EGFR and RET kinase inhibitor therapy (osimertinib and selpercatinib). The majority of patients benefitted from treatment with a response rate of 50%, a disease control rate of 83%, and a median treatment of duration 7.9 months, highlighting the potential use of the combination in clinic. On-target (second site EGFR or RET kinase domain mutations), off-target (ALK fusion, KRAS/BRAF mutation), and polyclonal resistance were observed. The authors propose that further treatment relapse can be mediated by competing clones harboring steric hindrance to EGFR/RET kinase engagement or non-EGFR/RET-mediated MAPK pathway reactivation. Low overall survival (OS) rates in post-treatment glioblastoma (GBM) patients highlight a need for new treatment options. Enrichment of immunosuppressive, extracellular-facing phosphatidylserine (PS) in GBM makes... You do not currently have access to this content.
Abstract IA025: The cell of origin is the dominant constraint in evolution of VHL related neoplasms
Authors: Scott Shepherd, Alex Coulton, Cathy Vocke, Chris Ricketts, Marston Linehan, Samra Turajlic
Journal: Cancer Research (2023)

Abstract Cancer is an evolutionary process, and an evolutionary framework can be used to decipher cancer initiation, progression and treatment resistance. In the context of VHL disease with repeat evolution of malignancies across different tissue contexts we can examine the factors that constrain tumour evolution. In the largest analysis of VHL-related tumours to date (1321 tumours across 132 patients), we observe the second hits on the background of germline VHL mutation vary and include loss of chromosome 3p, narrow deletion of VHL locus, VHL mutation or methylation. Pheochromocytomas and paragangliomas (PPGL) and solid renal tumours show a higher frequency of 3p loss, while pancreatic neuroendocrine tumors (PNETs) and renal cysts, exhibited a higher frequency of somatic VHL mutations, without 3p loss. Tumour size and progression were contingent on the nature of the second hit, suggesting potential evolutionary "dead-ends" where the tumor initiating event does not involve 3p loss. The type of germline VHL mutation (whether a complete deletion or missense) determined the distribution of cancers and their burden, but beyond this, multiple renal tumours in individual patients did not converge onto the same trajectory. This observation suggests that following malignant transformation evolutionary contingency and chance dominate tumour evolution. Metastases from renal tumours were driven by loss of chromosomes 9p and 14q, reminiscent of sporadic renal tumours, suggesting that acquisition of metastatic competence is associated with a high degree of bottlenecking and highlighting these events as important targets for metastasis prevention. Citation Format: Scott Shepherd, Alex Coulton, Cathy Vocke, Chris Ricketts, Marston Linehan, Samra Turajlic. The cell of origin is the dominant constraint in evolution of VHL related neoplasms [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA025.
Predicting the impact of sequence motifs on gene regulation using single-cell data
Authors: Jacob Hepkema, Nicholas Keone Lee, Benjamin J. Stewart, Siwat Ruangroengkulrith, Varodom Charoensawan, Menna R. Clatworthy, Martin Hemberg
Journal: Genome biology (2023)

The binding of transcription factors at proximal promoters and distal enhancers is central to gene regulation. Identifying regulatory motifs and quantifying their impact on expression remains challenging. Using a convolutional neural network trained on single-cell data, we infer putative regulatory motifs and cell type-specific importance. Our model, scover, explains 29% of the variance in gene expression in multiple mouse tissues. Applying scover to distal enhancers identified using scATAC-seq from the developing human brain, we identify cell type-specific motif activities in distal enhancers. Scover can identify regulatory motifs and their importance from single-cell data where all parameters and outputs are easily interpretable.
Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results
Authors: Alexander M. Lesokhin, Michael H. Tomasson, Bertrand Arnulf, Nizar J. Bahlis, H. Miles Prince, Ruben Niesvizky, Paula Rodrίguez-Otero, Joaquin Martinez-Lopez, Guenther Koehne, Cyrille Touzeau, Yogesh Jethava, Hang Quach, Julien Depaus, Hisayuki Yokoyama, Afshin Eli Gabayan, Don A. Stevens, Ajay K. Nooka, Salomon Manier, Noopur Raje, Shinsuke Iida, Marc-Steffen Raab, Emma Searle, Eric Leip, Sharon T. Sullivan, Umberto Conte, Mohamed Elmeliegy, Akos Czibere, Andrea Viqueira, Mohamad Mohty
Journal: Nature Medicine (2023)

Elranatamab is a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the ongoing phase 2 MagnetisMM-3 trial, patients with relapsed or refractory multiple myeloma received subcutaneous elranatamab once weekly after two step-up priming doses. After six cycles, persistent responders switched to biweekly dosing. Results from cohort A, which enrolled patients without prior BCMA-directed therapy (n = 123) are reported. The primary endpoint of confirmed objective response rate (ORR) by blinded independent central review was met with an ORR of 61.0% (75/123); 35.0% ≥complete response. Fifty responders switched to biweekly dosing, and 40 (80.0%) improved or maintained their response for ≥6 months. With a median follow-up of 14.7 months, median duration of response, progression-free survival and overall survival (secondary endpoints) have not been reached. Fifteen-month rates were 71.5%, 50.9% and 56.7%, respectively. Common adverse events (any grade; grade 3-4) included infections (69.9%, 39.8%), cytokine release syndrome (57.7%, 0%), anemia (48.8%, 37.4%), and neutropenia (48.8%, 48.8%). With biweekly dosing, grade 3-4 adverse events decreased from 58.6% to 46.6%. Elranatamab induced deep and durable responses with a manageable safety profile. Switching to biweekly dosing may improve long-term safety without compromising efficacy. ClinicalTrials.gov identifier: NCT04649359 .
Chronic kidney disease promotes atrial fibrillation via inflammasome pathway activation
Authors: Jia Song, Jose Alberto Navarro-Garcia, Jiao Wu, Arnela Saljic, Issam Abu-Taha, Luge Li, Satadru K. Lahiri, Joshua A. Keefe, Yuriana Aguilar-Sanchez, Oliver M. Moore, Yue Yuan, Xiaolei Wang, Markus Kamler, William E. Mitch, Gema Ruiz-Hurtado, Zhaoyong Hu, Sandhya S. Thomas, Dobromir Dobrev, Xander H.T. Wehrens, Na Li
Journal: Journal of Clinical Investigation (2023)

Chronic kidney disease (CKD) is associated with a higher risk of atrial fibrillation (AF). The mechanistic link between CKD and AF remains elusive. Interleukin (IL)-1β, a main effector of 'NLR-family pyrin domain-containing 3' (NLRP3) inflammasome activation, is a key modulator of conditions associated with inflammation, such as AF and CKD. Circulating IL-1β levels were elevated in CKD-patients with AF vs CKD-patients in sinus rhythm. Moreover, NLRP3-activity was enhanced in atria of CKD-patients. To elucidate the role of NLRP3/IL-1β signaling in the pathogenesis of CKD-induced AF, wildtype (WT) and Nlrp3-/- mice were subjected to a two-stage subtotal nephrectomy protocol to induce CKD. 4-weeks post-surgery, IL-1β levels in serum and atrial tissue were increased in WT-CKD (vs WT-sham) mice. The increased susceptibility to pacing-induced AF and longer AF-duration in WT-CKD mice were associated with electrical remodeling, enlarged atria, and atrial fibrosis. Genetic inhibition of NLRP3 in Nlrp3-/- mice or neutralizing anti-IL-1β antibodies effectively reduced IL-1β-levels, normalized left atrial dimensions, reduced fibrosis and the AF-incidence. These data suggest that CKD creates a substrate for AF development by activating the NLRP3 inflammasome in atria, which is associated with structural and electrical remodeling. Neutralizing IL-1β antibodies may be beneficial for the prevention of CKD-induced AF.
Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects
Authors: Sirle Saul, Marwah Karim, Luca Ghita, Pei-Tzu Huang, Winston Chiu, Verónica Durán, Chieh-Wen Lo, Sathish Kumar, Nishank Bhalla, Pieter Leyssen, Farhang Alem, Niloufar A. Boghdeh, Do H.N. Tran, Courtney A. Cohen, Jacquelyn A. Brown, Kathleen E. Huie, Courtney Tindle, Mamdouh Sibai, Chengjin Ye, Ahmed Magdy Khalil, Kevin Chiem, Luis Martinez-Sobrido, John M. Dye, Benjamin A. Pinsky, Pradipta Ghosh, Soumita Das, David E. Solow-Cordero, Jing Jin, John P. Wikswo, Dirk Jochmans, Johan Neyts, Steven De Jonghe, Aarthi Narayanan, Shirit Einav
Journal: Journal of Clinical Investigation (2023)

Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, 2 and 4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2-induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, pro-inflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production and disruption of the blood-brain barrier integrity in microfluidic-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof-of-principle for a repurposed, ErbB-targeted approach to combat emerging viruses.
Adverse outcomes in SARS-CoV-2–infected pregnant mice are gestational age–dependent and resolve with antiviral treatment
Authors: Patrick S. Creisher, Jamie L. Perry, Weizhi Zhong, Jun Lei, Kathleen R. Mulka, W. Hurley Ryan, Ruifeng Zhou, Elgin H. Akin, Anguo Liu, Wayne Mitzner, Irina Burd, Andrew Pekosz, Sabra L. Klein
Journal: Journal of Clinical Investigation (2023)

SARS-CoV-2 infection during pregnancy is associated with severe COVID-19 and adverse fetal outcomes, but the underlying mechanisms remain poorly understood. Moreover, clinical studies assessing therapeutics against SARS-CoV-2 in pregnancy are limited. To address these gaps, we developed a mouse model of SARS-CoV-2 infection during pregnancy. Outbred CD1 mice were infected at embryonic day (E) 6, E10, or E16 with a mouse adapted SARS-CoV-2 (maSCV2) virus. Outcomes were gestational age-dependent, with greater morbidity, reduced anti-viral immunity, greater viral titers, and impaired fetal growth and neurodevelopment occurring with infection at E16 (3rd trimester-equivalent) than with infection at either E6 (1st trimester-equivalent) or E10 (2nd trimester-equivalent). To assess the efficacy of ritonavir-boosted nirmatrelvir (recommended for pregnant individuals with COVID-19), we treated E16-infected dams with mouse equivalent doses of nirmatrelvir and ritonavir. Treatment reduced pulmonary viral titers, decreased maternal morbidity, and prevented offspring growth restriction and neurodevelopmental impairments. Our results highlight that severe COVID-19 during pregnancy and fetal growth restriction are associated with heightened virus replication in maternal lungs. Ritonavir-boosted nirmatrelvir mitigated maternal morbidity along with fetal growth and neurodevelopment restriction after SARS-CoV-2 infection. These findings prompt the need for further consideration of pregnancy in preclinical and clinical studies of therapeutics against viral infections.
Prolonged cytopenia following CD19 CAR T cell therapy is linked with bone marrow infiltration of clonally expanded IFNγ-expressing CD8 T cells
Authors: Paolo Strati, Xubin Li, Qing Deng, Mario L. Marques-Piubelli, Jared Henderson, Grace Watson, Laurel Deaton, Taylor Cain, Haopeng Yang, Vida Ravanmehr, Luis E. Fayad, Swaminathan P. Iyer, Loretta J. Nastoupil, Frederick B. Hagemeister, Edwin R. Parra, Neeraj Saini, Koichi Takahashi, Nathan H. Fowler, Jason R. Westin, Raphael E. Steiner, Ranjit Nair, Christopher R. Flowers, Linghua Wang, Sairah Ahmed, Gheath Al-Atrash, Francisco Vega, Sattva S. Neelapu, Michael R. Green
Journal: Cell Reports Medicine (2023)

Autologous anti-CD19 chimeric antigen receptor T cell (CAR T) therapy is highly effective in relapsed/refractory large B cell lymphoma (rrLBCL) but is associated with toxicities that delay recovery. While the biological mechanisms of cytokine release syndrome and neurotoxicity have been investigated, the pathophysiology is poorly understood for prolonged cytopenia, defined as grade ≥3 cytopenia lasting beyond 30 days after CAR T infusion. We performed single-cell RNA sequencing of bone marrow samples from healthy donors and rrLBCL patients with or without prolonged cytopenia and identified significantly increased frequencies of clonally expanded CX3CR1hi cytotoxic T cells, expressing high interferon (IFN)-γ and cytokine signaling gene sets, associated with prolonged cytopenia. In line with this, we found that hematopoietic stem cells from these patients expressed IFN-γ response signatures. IFN-γ deregulates hematopoietic stem cell self-renewal and differentiation and can be targeted with thrombopoietin agonists or IFN-γ-neutralizing antibodies, highlighting a potential mechanism-based approach for the treatment of CAR T-associated prolonged cytopenia.